This project seeks to further understand synaptic transmission and to characterize and define the molecular mechanisms of centrally acting depressant and convulsant drugs. The effects of these drugs will be investigated on the postsynaptic events of gamma-amino-butyric acid (GABA), which is a major inhibitory neurotransmitter in the mammalian CNS and central and peripheral nervous system of invertebrates. The approach to be utilized is: (a) to methodologically improve the in vitro assays for studying GABA post-synaptic responses which include receptor binding, ionophore binding and chloride permeability changes in mammalian brain and crayfish muscle, (b) characterize and develop spinal cord cultured cells as a model system for studying GABA synaptic pharmacology, (c) investigate the effects of depressant and convulsant drugs on these assays. GABA dysfunction may be responsible for a variety of neurological disorders and a variety of drugs, including benzodiazepenes, depressant barbiturates, convulsants and anticonvulsants have been implicated to act via the GABA synapse. A major emphasis of this project is to characterize, understand and define the molecular mode of action of barbiturates. The molecular mechanisms by which barbiturates produce CNS depression and unconsciousness are not known. A variety of barbiturates of different structures, different pharmacological activities and stereoisomers of some barbiturates which have opposite pharmacological activities will be employed to probe the site at the GABA receptor ionophore system at which they may act to modulate GABA synaptic events. The in vitro assays selected for this study will help us understand synaptic transmission, allow structure-activity relationship of drugs under study, provide screening tests for new GABA synaptic drugs and help us understand the mode of action of widely used depressant drugs. GABA synaptic pharmacology is at an infant stage and we are just beginning to probe it. A clearer understanding of synaptic transmission at the molecular level and the mechanism of centrally active drugs is fundamental to our understanding of normal biology, and development in the future of rational CNS therapy for neurological disorders.